Factors associated with poor outcomes among COVID-19 patients with gastrointestinal symptoms

Background & Aims Gastrointestinal (GI) symptoms are present in 20% of patients with COVID-19. We studied the association of GI symptoms (in COVID-19 patients) with adverse outcomes and factors associated with poor outcomes in these patients. Methods The study cohort included 100,902 patients from the Cerner Real World Data (CRWD) COVID-19 Database of hospital encounters and emergency department (ER) visits with COVID-19 infection from December 1, 2019, to November 30, 2020. Multivariate analysis was used to study the effect of GI symptoms on adverse outcomes, and the factors associated with acute respiratory distress syndrome (ARDS), sepsis, and ventilator requirement or oxygen dependence in COVID-19 patients with GI symptoms. Results Patients with COVID-19 and GI symptoms were significantly more likely to have ARDS (OR 1.20, 95% CI 1.11, 1.29), sepsis (OR 1.19, 95% CI 1.14, 1.24), acute kidney injury (OR 1.30, 95% CI 1.24, 1.36), venous thromboembolism (OR 1.36, 95% CI 1.22, 1.52) or GI bleed (OR 1.62, 95% CI 1.47, 1.79);and less likely to experience cardiomyopathy (OR 0.87, 95% CI 0.77, 0.99) or death (OR 0.71, 95% CI 0.67, 0.75). Among those with GI symptoms, older age, higher Charlson comorbidity index scores, and use of proton pump inhibitors (PPI)/ H2 receptor antagonists (H2RA) were associated with higher mortality, ARDS, sepsis, and ventilator or oxygen requirement. Conclusion Patients with COVID-19 who have GI symptoms have overall worse in-hospital complications, but less cardiomyopathy and mortality. Older age, higher comorbidity scores, and the use of PPI and H2RA are associated with poor outcomes in these patients.

Impact of age, sex, race, and regionality on major clinical outcomes of COVID-19 in hospitalized patients in the United States

The COVID-19 pandemic has affected all people across the globe. Regional and community differences in timing and severity of surges throughout the pandemic can provide insight into risk factors for worse outcomes in those hospitalized with COVID-19. The study cohort was derived from the Cerner Real World Data (CRWD) COVID-19 Database made up of hospitalized patients with proven infection from December 1, 2019 through November 30, 2020. Baseline demographic information, comorbidities, and hospital characteristics were obtained. We performed multivariate analysis to determine if age, race, comorbidity and regionality were predictors for mortality, ARDS, mechanical ventilation or sepsis hospitalized patients with COVID-19. Of 100,902 hospitalized COVID-19 patients included in the analysis (median age 52 years, IQR 36–67;50.7% female), COVID-19 case fatality rate was 8.5% with majority of deaths in those ≥ 65 years (70.8%). In multivariate analysis, age ≥ 65 years, male gender and higher Charlson Comorbidity Index (CCI) were independent risk factors for mortality and ARDS. Those identifying as non-Black or non-White race have a marginally higher risk for mortality (OR 1.101, CI 1.032–1.174) and greater risk of ARDS (OR 1.44, CI 1.334–1.554) when compared to those who identify as White. The risk of mortality or ARDS was similar for Blacks as Whites. Multivariate analysis found higher mortality risk in the Northeast (OR 1.299, CI 1.22–1.29) and West (OR 1.26, CI 1.18–1.34). Larger hospitals also had an increased risk of mortality, greatest in hospitals with 500–999 beds (OR 1.67, CI 1.43–1.95). Advanced age, male sex and a higher CCI predicted worse outcomes in hospitalized COVID-19 patients. In multivariate analysis, worse outcomes were identified in small minority populations, however there was no difference in study outcomes between those who identify as Black or White.

Ifit2 regulates murine-coronavirus spread to the spinal cord white matter and its associated myelin pathology (preprint)

Ifit2, an interferon-induced protein with tetratricopeptide repeats 2, plays a critical role in restricting neurotropic murine β-coronavirus RSA59 infection. RSA59 intracranial injection of Ifit2 deficient (-/-) compared to wild type (WT) mice results in impaired acute microglial activation, associated with reduced CX3CR1 expression, which consecutively limits migration of peripheral lymphocytes into the brain, leading to impaired virus control followed by severe morbidity and mortality. While the protective role of Ifit2 is established for acute viral encephalitis, less is known about its influence on demyelination during the chronic phase of RSA59 infection. Our current study demonstrates that Ifit2 deficiency causes extensive RSA59 viral spread throughout both the spinal cord grey and white matter and is associated with impaired CD4 + T cell infiltration. Cervical lymph nodes of RSA59 infected Ifit2 -/- mice showed reduced activation of CD4 + T cells and impaired IFNγ expression during acute encephalomyelitis. Furthermore, blood-brain-barrier integrity was preserved in the absence of Ifit2 as evidenced by integral, tight junction protein ZO-1 expression surrounding the meninges and blood vessels and decreased Texas red dye uptake. In contrast to WT mice exhibiting only sparse myelin loss, the chronic disease phase in Ifit2 -/- mice was associated with severe demyelination and persistent viral load, even at low infection doses. Overall, our study highlights that Ifit2 provides antiviral functions by promoting acute neuroinflammation and thereby aiding virus control and limiting severe demyelination. Author Summary The role of interferons in providing protective immunity against viral spread and pathogenesis is well known. Interferons execute their function by inducing certain genes collectively called as interferon stimulated genes (ISGs) among which Interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is known for restricting neurotropic viral replication and spread in the brain. So far, not much has been investigated about its role in viral spread to the spinal cord and its associated myelin pathology. Towards this our study using neurotropic murine-β-coronavirus and Ifit2 deficient mice demonstrate that Ifit2 deficiency causes extensive viral spread throughout grey and white matter of spinal cord accompanied by impaired microglial activation and CD4 + T cell infiltration. Furthermore, infected Ifit2 deficient mice showed impaired activation of T cells in cervical lymph node and Blood-Brain-Barrier was relatively intact. Ifit2 deficient mice developed viral induced severe chronic neuroinflammatory demyelination accompanied by the presence of ameboid shaped phagocytotic microglia/macrophages.

Mitoquinone mesylate targets SARS-CoV-2 and associated lung inflammation through host pathways (preprint)

To date, there is no effective oral antiviral against SARS-CoV-2 that is also anti-inflammatory. Herein, we show that the mitochondrial antioxidant mitoquinone/mitoquinol mesylate (Mito-MES), a dietary supplement, has potent antiviral activity against SARS-CoV-2 and its variants of concern in vitro and in vivo. Mito-MES had nanomolar in vitro antiviral potency against the Beta and Delta SARS-CoV-2 variants as well as the murine hepatitis virus (MHV-A59). Mito-MES given in SARS-CoV-2 infected K18-hACE2 mice through oral gavage reduced viral titer by nearly 4 log units relative to the vehicle group. We found in vitro that the antiviral effect of Mito-MES is attributable to its hydrophobic dTPP+ moiety and its combined effects scavenging reactive oxygen species (ROS), activating Nrf2 and increasing the host defense proteins TOM70 and MX1. Mito-MES was efficacious reducing increase in cleaved caspase-3 and inflammation induced by SARS-CoV2 infection both in lung epithelial cells and a transgenic mouse model of COVID-19. Mito-MES reduced production of IL-6 by SARS-CoV-2 infected epithelial cells through its antioxidant properties (Nrf2 agonist, coenzyme Q10 moiety) and the dTPP moiety. Given established safety of Mito-MES in humans, our results suggest that Mito-MES may represent a rapidly applicable therapeutic strategy that can be added in the therapeutic arsenal against COVID-19. Its potential long-term use by humans as diet supplement could help control the SARS-CoV-2 pandemic, especially in the setting of rapidly emerging SARS-CoV-2 variants that may compromise vaccine efficacy. One-Sentence SummaryMitoquinone/mitoquinol mesylate has potent antiviral and anti-inflammatory activity in preclinical models of SARS-CoV-2 infection.

The ApoA-I mimetic peptide 4F attenuates in vitro replication of SARS-CoV-2, associated apoptosis, oxidative stress and inflammation in epithelial cells.

An oral antiviral against SARS-CoV-2 that also attenuates inflammatory instigators of severe COVID-19 is not available to date. Herein, we show that the apoA-I mimetic peptide 4 F inhibits Spike mediated viral entry and has antiviral activity against SARS-CoV-2 in human lung epithelial Calu3 and Vero-E6 cells. In SARS-CoV-2 infected Calu3 cells, 4 F upregulated inducers of the interferon pathway such as MX-1 and Heme oxygenase 1 (HO-1) and downregulated mitochondrial reactive oxygen species (mito-ROS) and CD147, a host protein that mediates viral entry. 4 F also reduced associated cellular apoptosis and secretion of IL-6 in both SARS-CoV-2 infected Vero-E6 and Calu3 cells. Thus, 4 F attenuates in vitro SARS-CoV-2 replication, associated apoptosis in epithelial cells and secretion of IL-6, a major cytokine related to COVID-19 morbidity. Given established safety of 4 F in humans, clinical studies are warranted to establish 4 F as therapy for COVID-19.